PROJECT SUMMARY Treatment of Major Depressive Disorder (MDD) is a serious clinical challenge as nearly 50% of depressed patients do not fully respond to treatment, referred to as Treatment Resistant Depression (TRD). Current antidepressants take few weeks to work and further, there are no reliable clinical biomarkers available to predict treatment response which leads to several trial-and-error attempts of different treatment strategies. The two leading challenges in MDD research are ? (i) developing better treatments and (ii) developing noninvasive clinically useful biomarkers of antidepressant treatment response. The main objective of this award is to investigate prefrontal cortical excitability as neurobiological mechanisms underlying depression and antidepressant effect of rTMS in patients with TRD by using concurrent Transcranial Magnetic Stimulation- Electroencephalography (TMS-EEG). This project uses an innovative research strategy by deploying TMS-EEG to study cortical excitability in dorsolateral prefrontal cortex in TRD patients at baseline and after intermittent theta burst stimulation (iTBS), a state-of-the-art FDA approved TRD treatment. For baseline comparison with patients, demographically matched healthy controls will have TMS-EEG. The project aims will be accomplished by: 1) Investigating the prefrontal cortical excitability in patients with depression compared with healthy control subjects; 2) Investigating the effect of iTBS on prefrontal cortical excitability; and 3) Investigating the baseline dorsolateral prefrontal cortical excitability measures and its relationship to improvements in mood in patients with TRD. The findings from this study will strengthen our understanding of mechanisms underlying anti-depressant action and thus facilitate development of non-invasive surrogate markers of antidepressant response to iTBS in TRD. This work will contribute to: 1) personalized medicine in MDD by establishing markers of treatment response, 2) understanding rTMS antidepressant effect.